Submissions for variant NM_000492.4(CFTR):c.2245C>T (p.Leu749=)

gnomAD frequency: 0.00056  dbSNP: rs151235408

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000247513	SCV000304478	likely benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV001085588	SCV000625731	likely benign	Cystic fibrosis	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586139	SCV000696891	likely benign	not provided	2016-04-20	criteria provided, single submitter	clinical testing	Variant summary: The variant affects a conserved nucleotide and results in a synonymous mutation. 5/5 in silico tools predict the variant not to have an impact on splicing while mutation taster predicts the variant to be disease causing. It was predominantly observed in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.096% which does not exceed the maximal expected allele frequency of a disease causing CFTR allele (1.3%). It has been reported in patients with wide spectrum of CFTR-related disorders (CF, CBAVD, asthma and COPD) as well as in healthy population and often reported as polymorphism. In one CBAVD patient, this variant was found in cis with R764X (Pallares-Ruiz_1999). In addition, according to Bombieri, it does not lead to exon skipping, suggesting it is indeed not pathogenic. Considering all evidence, the variant was classified as Likely Benign.
Eurofins Ntd Llc (ga)	RCV000586139	SCV000703406	uncertain significance	not provided	2017-08-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586139	SCV000883595	benign	not provided	2023-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001085588	SCV001175682	likely benign	Cystic fibrosis	2015-04-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001163688	SCV001325752	uncertain significance	CFTR-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001085588	SCV001822097	likely benign	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Reproductive Genetics, University of Münster	RCV001640481	SCV001860335	likely benign	Obstructive azoospermia	2021-12-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586139	SCV001962091	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	CFTR: BP4, BP7
Sema4, Sema4	RCV002255346	SCV002529688	likely benign	Hereditary pancreatitis	2021-01-10	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586139	SCV004221672	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 24782259 (2021) and 7689013 (1993)), emphysema (PMID: 9921909 (1998)), and congenital bilateral absence of the vas deferens (CBAVD) and oligoasthenoteratozoospermia (OAT) (PMID: 10601093 (1999)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001085588	SCV001338837	likely benign	Cystic fibrosis	2020-02-28	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001085588	SCV001455987	likely benign	Cystic fibrosis	2020-06-11	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586139	SCV001958666	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586139	SCV001963624	likely benign	not provided		no assertion criteria provided	clinical testing